The present invention relates to a process for producing xcex1-amino-dihalogenated methyl ketone derivatives from N-protected xcex1-amino acid esters.
The present invention also relates to a process for producing xcex2-amino-xcex1-hydroxycarboxylic acid derivatives from the xcex1-amino-dihalogenated methyl ketone derivatives.
It was reported that xcex1-amino-dihalogenated methyl ketone derivatives can be easily converted into xcex2-amino-xcex1-hydroxycarboxylic acid derivatives by hydrolysis in the presence of a base (see J.P. KO-KAI No. Hei 10-59909). xcex2-Amino-xcex1-hydroxycarboxylic acid derivatives obtained by this reaction are important compounds as intermediates for inhibitors of enzymes, such as HIV protease and renin or for some anticancer drugs (see, for example, Chem. Pharm. Bull. 1992, 40, 2251, J. Med. Chem. 1990, 33, 2707, Biochem. Pharmacol. 1983, 32, 1051, and Bull. Cancer 1993, 80, 326).
As for processes for producing xcex1-amino-dihalogenated methyl ketone derivatives, it is described in an Example of J.P. KOKAI No. Hei 10-59909 that an N-carbamate-protected xcex1-amino-dichloromethyl ketone derivative is produced by treating an xcex1-amino-monochloromethyl ketone derivative, in which the amino group is protected with a carbamate-type protecting group, with sulfuryl chloride. However, this process is unsuitable for the production of a compound having a protecting group (such as t-butoxycarbonyl group) for an amino group, which is unstable against acids, because a strong acid is formed in the reaction system. In addition, the production of N-carbamate-protected xcex1-amino-monochloromethyl ketone derivatives used as the starting material is not always easy.
The object of the present invention is to provide an economical, efficient process for producing xcex1-amino-dihalogenated methyl ketone derivatives and xcex2-amino-xcex1-hydroxycarboxylic acid derivatives on an industrial scale.
After intensive investigations made for the purpose of solving the above-described problems, the inventors have found that xcex1-amino-dihalogenated methyl ketones can be easily obtained by reacting an N-protected xcex1-amino acid ester with a dihalomethyl lithium. The present invention has been completed on the basis of this finding.
Namely, the present invention provides a process for producing xcex1-amino-dihalogenated methyl ketone derivatives of the following general formula (3): 
wherein B3 and B4 independently represent a hydrogen atom or a protecting group for an amino group, or B3 and B4 together form an imine-type protecting group; A represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20 carbon atoms, or a group corresponding thereto which contains a hetero atom in the carbon skeleton; and X1 and X2 independently represent a chlorine atom or a bromine atom,
which comprises the step of reacting an N-protected xcex1-amino acid ester of following general formula (1): 
wherein B1 and B2 independently represent a hydrogen atom or a protecting group for an amino group, or B1 and B2 together form an imine-type protecting group (with the proviso that both B1 and B2 cannot be hydrogen atom at the same time), R1 represents an unsubstituted or substituted lower alkyl group, aralkyl group or aryl group, and A is as defined above,
with a dihalomethyl lithium of general formula (2) 
wherein X1 and X2 are as defined above.
The present invention also provides a process for producing xcex2-amino-xcex1-hydroxycarboxylic acid derivatives of general formula (4): 
wherein B5 and B6 independently represent a hydrogen atom or a protecting group for an amino group, or B5 and B6 together form an imine-type protecting group, and A represents hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20 carbon atoms, or a group corresponding thereto which contains a hetero atom in the carbon skeleton,
which comprises the steps of hydrolyzing an xcex1-amino-dihalogenated methyl ketone derivative in the presence of a base and protecting or not protecting the amino group.
In the formulae in the present invention, B1 and B2 independently represent a hydrogen atom or a protecting group for an amino group, or B1 and B2 together form an imine-type protecting group. However, both B1 and B2 cannot be hydrogen atom at the same time.
The protecting group for amino group is not particularly limited. For example, protecting groups described in Protecting Groups in Organic Chemistry, 2nd Edition (John Wiley and Sons, Inc. 1991) are usable. The protecting groups are, for example, carbamate-type protecting groups such as a methoxycarbonyl group, a ethoxycarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, and a fluorenylmethoxycarbonyl group; acyl-type protecting groups such as an acetyl group and a benzoyl group; sulfonyl-type protecting groups, such as a methanesulfonyl group, a benzenesulfonyl group, and a p-toluenesulfonyl group; alkyl-type protecting groups, such as a benzyl group and a p-methoxybenzyl group; dialkyl-type protecting groups, such as, a dibenzyl group; silyl-type protecting groups, such as, a trimethylsilyl group; and imine-type protecting groups, such as, a diphenylmethylene group, a phenylmethylene group, and a p-methoxyphenylmethylene group. Among them, carbamate-type protecting groups are preferred because they can be easily removed.
When B1 and B2 together form an imine-type protecting group, N-protected xcex1-amino acid esters of general formula (1) can be represented by following general formula (6): 
wherein R2 and R3 independently represent an unsubstituted or substituted aryl group or lower alkyl group or hydrogen atom, or R2 and R3 may be bonded together directly or via a suitable group to form a ring structure.
Examples of the ring structures include the following structures (16) and (17): 
[Formulae (16) and (17) include both protecting group formed by R2 and R3 and the imine structure].
Preferably R2 and R3 each represent an unsubstituted or substituted aryl group or one of them represents an unsubstituted or substituted aryl group and the other represents a hydrogen atom.
The unsubstituted or substituted lower alkyl group, aralkyl group or aryl group represented by R1 in the formula in the present invention include unsubstituted or substituted, linear or branched, saturated alkyl groups having 1 to 8 carbon atoms, unsubstituted or substituted aralkyl groups having 7 to 15 carbon atoms, and unsubstituted or substituted aryl groups having 6 to 14 carbon atoms. R1 is preferably an unsubstituted or substituted lower alkyl group, or aralkyl group. R1 is particularly preferably a linear or branched, saturated alkyl group having 1 to 3 carbon atoms, i.e. methyl group, ethyl group, propyl group, isopropyl group or unsubstituted or substituted benzyl group. When the benzyl group is substituted, the substituent is an alkoxyl group (preferably having 1 to 7 carbon atoms), nitro group, an alkyl group (preferably having 1 to 6 carbon atoms), a halogen atom or the like.
A in the formulae in the present invention represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20 carbon atoms, or a corresponding group which further contains a hetero atom in the carbon skeleton. When those groups have a substituent, the substituent is an alkoxyl group (preferably having 1 to 7 carbon atoms), a nitro group, an alkyl group (preferably having 1 to 6 carbon atoms), a halogen atom or the like.
Such a group can be introduced into the compound from, e.g., an amino acid. For example, when A is hydrogen atom, it can be introduced by using glycine as the starting material. In the same way, a methyl group can be introduced by using alanine; an isopropyl group can be introduced by using valine; a 2-methylpropyl group can be introduced by using leucine; a 1-methylpropyl group can be introduced by using isoleucine; a benzyl group can be introduced by using phenylalanine; and a methylthioethyl group can be introduced by using methionine.
A may be a group introduced by using an amino acid in which a functional group in a side chain thereof is protected, such as S-t-butylcysteine, S-tritylcysteine, S-(p-methylbenzyl)cysteine, S-(p-methoxybenzyl)cysteine, O-t-butylserine, O-benzylserine, O-t-butylthreonine, O-benzylthreonine, O-t-butyltyrosine or O-benzyltyrosine, as the starting material.
A is not limited to a group introduced from a starting material derived from a natural amino acid, but it may a group introduced from a starting material derived from a synthetic amino acid (such as a cyclohexylmethyl group, a phenyl group, or a phenylthiomethyl group).
Preferably A represents an unsubstituted or substituted alkyl group having 1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20 carbon atoms, or a group corresponding thereto which contains a hetero atom in the carbon skeleton.
In the formulae in the present invention, X1 and X2 independently represent a chlorine atom or a bromine atom. It is preferred that both X1 and X2 represent chlorine atom or bromine atom. It is particularly preferred that both X1 and X2 represent chlorine atom.
In the formula in the present invention, B3 and B4 independently represent hydrogen atom or a protecting group for amino group, or B3 and B4 together form an imine-type protecting group. The protecting groups for amino group are as described above. The imine-type protecting groups are also as described above.
In the formula in the present invention, B5 and B6 independently represent a hydrogen atom or a protecting group for an amino group, or B5 and B6 together form an imine-type protecting group. The protecting groups for amino group are as described above. The imine-type protecting groups are also as described above.
N- protected xcex1-amino acid esters of general formula (1) used as the starting material in the present invention can be produced from xcex1-amino acid esters and salts thereof or xcex1-amino acids by a known process.
N-carbamate-protected xcex1-amino acid esters particularly preferably used as the starting compounds in the present invention can be easily synthesized from xcex1-amino acid esters and salts thereof by an ordinary technique of synthesizing peptides.
When N-protected xcex1-amino acid esters of general formula (1) are in a form protected with an imine-type protecting group as shown in above general formula (6), they can be easily produced from an xcex1-amino acid ester of general formula (7) or a salt thereof and an imine compound of general formula (8) or an aldehyde or ketone compound of general formula (9) by a known method (see, for example, A. Dondoni et al., Synthesis 1993, 1162 and M. J. O""Donnel et al., J. Org. Chem. 1982, 47, 2663) according to the following scheme: 
wherein R1, R2, R3 and A are as defined above.
The production process of the present invention can be employed for synthesizing optically active compounds by using an optically active xcex1-amino acid ester obtained by esterifying an optically active amino acid. Optically active amino acids are important in the field of medicines. Namely, optically active compounds (L- and D-compounds) are preferably used as the xcex1-amino acid esters. In particular, optically active phenylalanine esters are important starting materials of HIV protease inhibitors.
Now, the description will be made on the process for producing xcex1-amino-dihalogenated methyl ketones of general formula (3) by reacting an N-protected xcex1-amino acid ester of general formula (1) with a dihalomethyl lithium of general formula (2).
A dihalomethyl lithium of general formula (2) can be produced from a dihalomethane of general formula (10) and a lithium amide of general formula (11) according to the following scheme: 
wherein X1 and X2 are as defined above, R4 and R5 independently represent an alkyl group or a trialkylsilyl group and R4 and R5 may be bonded together directly or via a suitable group to form a ring structure.
Examples of the alkyl groups include a methyl group, an ethyl group, an isopropyl group, and a cyclohexyl group. The trialkylsilyl groups include, for example, a trimethylsilyl group. An example of the ring structures is shown by the following formula (12): 
The dihalomethane of general formula (10) is any of dichloromethane, dibromomethane and bromochloromethane. Preferred examples of the lithium amides of general formula (11) include lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, lithium dicyclohexylamide, lithium 2,2,6,6-tetramethyl piperidide and lithium bis(trimethylsilyl)amide. Lithium diisopropylamide is particularly preferred.
It is known from U.S. Pat. No. 5,481,011 and Tetrahedron Letters, 38, 3175-3178, 1997 that an N-protected xcex1-amino acid ester is reacted with chloroiodomethane and lithium diisopropylamide to form N-protected xcex1-amino-monochloromethyl ketone. In this reaction, an exchange reaction of an iodine atom with lithium must be carried out in the obtained intermediate in order to obtain monochloromethyl ketone (see the reaction scheme on page 3175 of the above-described Tetrahedron Letters).
According to the Tetrahedron Letters publication (38, 3175-3178, 1997), at least 4 equivalents of chloroiodomethane and also at least 4 equivalents of lithium diisopropylamide are [necessitated] necessary. It is described therein that for attaining the optimum conditions, 4 equivalents of chloroiodomethane and 5 equivalents of lithium diisopropylamide are to be used.
In the present invention, such an exchange reaction must be prevented for synthesizing N-protected xcex1-amino-dihalomethyl ketones. Namely, in the present invention, the amount of a dihalomethyl lithium (particularly dibromomethyl lithium or bromochloromethyl lithium) to be reacted with an N-protected xcex1-amino acid ester is preferably 2 equivalents to less than 3 equivalents, more preferably 2.2 equivalents to 2.8 equivalents, particularly 2.4 equivalents to 2.6 equivalents.
Therefore, in the production of a dihalomethyl lithium from a dihalomethane and a lithium amide, the amount of each of dihalomethane and lithium amide is preferably 2 equivalents to less than 3 equivalents, more preferably 2.2 equivalents to 2.8 equivalents, particularly 2.4 equivalents to 2.6 equivalents.
In the production of an N-protected xcex1-amino-dihalomethyl ketone from an N-protected xcex1-amino acid ester and dichloromethyllithium, the above-described exchange reaction does not occur.
In the dihalomethyl lithiums, dichloromethyl lithium can be produced from dichloromethane and an organic lithium of general formula (13) according to the following scheme: 
wherein R6 represents a lower alkyl group or an aryl group.
The lower alkyl groups include a linear or branched, saturated alkyl groups having 1 to 8 carbon atoms. Linear, saturated alkyl groups having 1 to 6 carbon atoms, i.e. a methyl group, an ethyl group, an n-butyl group, a sec-butyl group, and a n-hexyl group, are particularly preferred.
The aryl groups are, for example, a phenyl group and a naphthyl group.
Lower alkyllithiums of the above formula wherein R6 represents a lower alkyl group are preferred. Those where R6 represents a linear, saturated alkyl group having 1 to 6 carbon atoms, i.e. a methyl group, an ethyl group, an n-butyl group, a sec-butyl group, and a n-hexyl group, are particularly preferred.
The N-protected xcex1-amino acid ester is reacted with the dihalomethyl lithium.
The following two reaction procedures are possible:
(1) A dihalomethyl lithium is previously produced by reacting a lithium amide or an organic lithium compound with a dihalomethane. Then, an N-protected xcex1-amino acid ester is added thereto. When both B1 and B2, which are protecting groups for amino group, are not hydrogen [atom] atoms, this reaction procedure is preferred. The reaction temperature is preferably about xe2x88x92120xc2x0 C. to xe2x88x9250xc2x0 C.
(2) A dihalomethane is reacted with a lithium amide or an organic lithium compound in the presence of an N-protected xcex1-amino acid ester to form a dihalomethyllithium in the reaction system. The reaction temperature is preferably about xe2x88x92120xc2x0 C. to +10xc2x0 C. The reaction can be carried out at a relatively high temperature such as xe2x88x9220xc2x0 C.
When this reaction procedure is employed, a carbamate-type protecting group is preferred.
The reaction solvent is preferably an ether solvent such as tetrahydrofuran, diethyl ether, or t-butyl methyl ether. If necessary, the solvent can be used in the form of a mixture thereof with a non-polar solvent, such as toluene or hexane. The reaction rapidly proceeds at a temperature of about xe2x88x92120xc2x0 C. to +10xc2x0 C. Usually, the reaction is completed at xe2x88x9280xc2x0 C. to xe2x88x9220xc2x0 C. in 5 to 60 minutes. After the completion of the reaction, the reaction mixture is treated with an aqueous ammonium chloride solution, a phosphate buffer, a dilute hydrochloric acid solution, a dilute sulfuric acid solution, or the like.
The protecting group for the amino group is either removed or not removed depending on the combination of the reaction conditions with the protecting group. The amino group may be kept as it is without the protecting group or another protecting group may be introduced by a well-known method. The carbamate-type protecting group preferably used in the present invention can be usually kept as it is when the compound is reacted as will be described in the Examples given below.
Then, the reaction product is extracted from the reaction solution with a solvent such as ethyl acetate, diethyl ether, toluene, isopropyl acetate, tert-butyl methyl ether, dichloromethane, or chloroform. Then, if necessary, the obtained solution is concentrated (or evaporated). If necessary, a solvent such as methanol, ethanol, 2-propanol, acetonitrile, tetrahydrofuran, hexane, heptane or acetone is added to the product. The obtained solution is heated to about 40 to 80xc2x0 C. The xcex1-amino-dihalogenated methyl ketone derivative can be obtained in solid form by the crystallization by cooling to a temperature of xe2x88x9220xc2x0 C. to room temperature or by a chromatography. The product may be used for the subsequent reaction without being separated or purified.
xcex1-Amino-dihalogenated methyl ketone derivatives of general formula (3) can be easily converted into, xcex2-amino-xcex1-hydroxycarboxylic acid derivatives by hydrolysis in the presence of a base, as described in J. P. KOKAI No. Hei 10-59909. In this case, the protecting group for the amino group is either removed or kept depending on the combination of the reaction conditions with the protecting group. The compound thus obtained may be isolated as it is without the protecting group or another protecting group may be introduced. When another protecting group is introduced, the introduction can be conducted by, for example, a process described in J. P. KOKAI No. Hei 10-59909. xcex2-amino-xcex1-hydroxycarboxylic acid derivatives are important compounds as intermediates for enzyme inhibitors, such as HIV protease and rennin, or some anticancer drugs.
The compounds in the present invention also include racemic compounds and both optically active compounds. When an optically active N-protected xcex1-amino acid ester is used as the N-protected xcex1-amino acid ester of general formula (1), a compound of general formula (3) obtained by the process of the present invention maintains its optical activity. Further, compounds of general formula (4) produced from the above-described compounds of general formula (3) also maintain their optical activity. Therefore, the process of the present invention is very useful for the synthesis of intermediate compounds for medicines.
The following Examples will further illustrate the present invention, which by no means limit the invention.